Structural and functional imaging studies have significantly impacted our understanding of the neural basis of developmental and neurological disorders. However, despite recent advancements, anatomical imaging in autistic patients has generally revealed little evidence of pathology, except evidence of transient increase in brain size along with some evidence of reduced corpus callosum and cerebellum size. These anatomical features and some fMRI studies have hypothesized a state of disrupted connectivity in the autistic brain that may be responsible for the behavioral traits observed in autism. To test this hypothesis, and to better understand the mechanistic role of brain connectivity in autism-related behavioral phenotypes, we will employ diffusion tensor imaging (DTI) techniques in mouse models as a surrogate for better diagnosis of the disorder. While DTI has been extensively used in human subjects, it would be extremely useful to develop this methodology for rodents as the mouse is an excellent model to probe the relationship between brain structure and social/behavioral patterns in a well controlled environment and provides tissue for histological confirmation. While, a true animal model of autism may be impossible to achieve, both inbred mice and mice with specific genetic mutations have been suggested to exhibit some endophenotypical behaviors observed in autistic patients indicative of their utility as relevant models for studying autism spectrum disorders. We will study the DTI properties in an inbred (BALB/cJ) and a mutant (neuroligin-3) strain of mice as these models have been shown to exhibit multiple behavioral and brain phenotypes relevant to autism, including reduced sociability and underdevelopment of the corpus callosum. We will test the overall hypothesis that longitudinal changes in DTI parameters can detect specific anatomical disruptions that underlie autism-relevant behavioral phenotypes in mouse models. The following specific aims will be achieved in order to support this hypothesis: Aim 1: To determine the utility of DTI as surrogate markers for assessing developmental changes (from prepubescence to early adulthood) in brain connectivity and social-behavior patterns of BALB/cJ mice. Aim 2: To determine the correlation between DTI features and social behaviors associated with the Nl-3 gene knockin mice and their longitudinal changes over pubescence. Longitudinal in vivo DTI studies (from pre-pubescence to early adulthood) will be performed to measure the changes in DTI metrics from the brain using a voxel based analysis. Correlations between DTI metrics and sociability will be tested in each group. After each in vivo session, some mice will be sacrificed and brains will be isolated and high- resolution ex vivo DTI studies will be performed and correlated with histological measurements. Successful implementation of the DTI techniques in the mouse in vivo will not only be helpful in understanding the biological and physiological basis of autism spectrum disorders, but will also benefit studies of other mouse models of developmental and psychiatric brain disorders, such as schizophrenia. PUBLIC HEALTH RELEVANCE: In this proposal high-resolution diffusion tensor imaging of the mouse brain will be developed as surrogate markers to assess the social behavioral abnormalities in mouse models relevant to autism. Successful implementation of the proposed DTI techniques in these models will not only be helpful in understanding the biological and physiological basis of autism spectrum disorders, but will also benefit studies of other mouse models of developmental and psychiatric brain disorders, such as schizophrenia.